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Local Administration of GITR Agonistic Antibody Induces a Stronger Antitumor Immunity than Systemic Delivery.

ABSTRACT: An anti-glucocorticoid induced TNF receptor (GITR) agonistic antibody (Ab) induces an antitumor immunity with both stimulation of effector T cells and inhibition of regulatory T cell activity. To enhance GITR Ab-mediated tumor immunity, we focused on the intratumoral route, since a tumor-localized high concentration of Ab would confer activation of only tumor-infiltrating T cells. First, in a murine colon cancer model, we showed that the intratumoral delivery of Ab significantly increased the number of effector T cells infiltrated into tumors, and suppressed tumor growth more effectively than the intraperitoneal and intravenous injections did. Then, we found that the injection of Ab into the peritumoral area induced a systemic antitumor immunity at a similar level to the intratumoral injection. Therefore, we hypothesized that the transfer of locally administrated Ab into tumor-draining lymph nodes (TDLNs) plays an important role in inducing an effective immunity. In fact, intratumorally or peritumorally injected Ab was detected in TDLNs, and resection of Ab-injected TDLNs significantly reduced GITR Ab-mediated systemic tumor immunity. Intratumoral injection showed less number of auto-reactive T cells in the spleen than the intraperitoneal injection did. Intratumoral delivery of GITR Ab is a promising approach to induce an effective immunity compared to the systemic delivery.

SUBMITTER: Narumi K

PROVIDER: S-EPMC6447616 | biostudies-literature | 2019 Apr

REPOSITORIES: biostudies-literature

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Local Administration of GITR Agonistic Antibody Induces a Stronger Antitumor Immunity than Systemic Delivery.

Narumi Kenta K Miyakawa Reina R Shibasaki Chihiro C Henmi Marina M Mizoguchi Yukihiro Y Ueda Ryosuke R Hashimoto Hisayoshi H Hiraoka Nobuyoshi N Yoshida Teruhiko T Aoki Kazunori K

Scientific reports 20190403 1

An anti-glucocorticoid induced TNF receptor (GITR) agonistic antibody (Ab) induces an antitumor immunity with both stimulation of effector T cells and inhibition of regulatory T cell activity. To enhance GITR Ab-mediated tumor immunity, we focused on the intratumoral route, since a tumor-localized high concentration of Ab would confer activation of only tumor-infiltrating T cells. First, in a murine colon cancer model, we showed that the intratumoral delivery of Ab significantly increased the nu ...[more]

PMID: 30944344

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Project description:BackgroundColorectal cancer (CRC) is one of the most common malignancies and the patient survival rate remains unacceptably low. The anti-programmed cell death-1 (PD-1)/programmed cell death ligand 1 (PD-L1) antibody-based immune checkpoint inhibitors have been added to CRC treatment regimens, however, only a fraction of patients benefits. As an important co-stimulatory molecule, 4-1BB/CD137 is mainly expressed on the surface of immune cells including T and natural killer (NK) cells. Several agonistic molecules targeting 4-1BB have been clinically unsuccessful due to systemic toxicity or weak antitumor effects. We generated a humanized anti-4-1BB IgG4 antibody, HuB6, directed against a unique epitope and hypothesized that it would promote antitumor immunity with high safety.MethodsThe antigen binding specificity, affinity and activity of HuB6 were determined by enzyme-linked immunosorbent assay (ELISA), surface plasmon resonance (SPR), biolayer interferometry (BLI) and flow cytometry. The antitumor effects were evaluated in humanized mice bearing syngeneic tumors, and possible toxicity was evaluated in humanized mice and cynomolgus monkeys.ResultsHuB6 showed high specificity and affinity for a binding epitope distinct from those of other known 4-1BB agonists, including utomilumab and urelumab, and induced CD8 + T, CD4 + T and NK cell stimulation dependent on Fcγ receptor (FcγR) crosslinking. HuB6 inhibited CRC tumor growth in a dose-dependent manner, and the antitumor effect was similar with urelumab and utomilumab in humanized mouse models of syngeneic CRC. Furthermore, HuB6 combined with an anti-PD-L1 antibody significantly inhibited CRC growth in vivo. Additionally, HuB6 induced antitumor immune memory in tumor model mice rechallenged with 4 × 106 tumor cells. Toxicology data for humanized 4-1BB mice and cynomolgus monkeys showed that HuB6 could be tolerated up to a 180 mg/kg dose without systemic toxicity.ConclusionsThis study demonstrated that HuB6 should be a suitable candidate for further clinical development and a potential agent for CRC immunotherapy.

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Local Administration of GITR Agonistic Antibody Induces a Stronger Antitumor Immunity than Systemic Delivery.

Publications

Local Administration of GITR Agonistic Antibody Induces a Stronger Antitumor Immunity than Systemic Delivery.

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